Dodecyl creatine ester improves cognitive function and identifies key protein drivers including KIF1A and PLCB1 in a mouse model of creatine transporter deficiency.

Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical in vitro and in vivo data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8-/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content. Shotgun proteomics analysis of 4,035 proteins in four different brain regions; the cerebellum, cortex, hippocampus (associated with cognitive functions) and brain stem, and muscle as a control, was performed in 24 mice. Comparison of the protein abundance in the four brain regions between DCE-treated intranasally Slc6a8-/y mice and wild type and DCE-treated Slc6a8-/y and vehicle group identified 14 biomarkers, shedding light on the mechanism of action of DCE. Integrative bioinformatics and statistical modeling identified key proteins in CTD, including KIF1A and PLCB1. The abundance of these proteins in the four brain regions was significantly correlated with both the object recognition and the Y-maze tests. Our findings suggest a major role for PLCB1, KIF1A, and associated molecules in the pathogenesis of CTD.

The papillary muscle sling for ischemic mitral regurgitation.

OBJECTIVE: Our objective was to evaluate long-term stability of mitral repair and reverse remodeling in patients with severe ischemic left ventricular dysfunction and functional mitral regurgitation. METHODS: Since June 2000, a total of 37 patients with ischemic functional mitral regurgitation have benefited from a double-level mitral repair that comprises an intraventricular peripapillary muscle sling completed by a classic intra-atrial mitral annuloplasty ring (mean age, 56 years; left ventricular end-diastolic diameter, 70 +/- 0 mm; left ventricular end-systolic diameter, 55 +/- 5.6 mm; ejection fraction, 15% to 45%; pulmonary hypertension > 60 in all patients; all were in New York Heart Association class III-IV). All patients had both papillary muscles encircled with a 4-mm polytetrafluoroethylene tube, correcting their lateral and downward displacement. Annuloplasty rings were moderately undersized or normal. Efficiency was evaluated on mitral stability, ventricular parameters, and functional status. According to the Leyden algorithm based on preoperative end-diastolic and end-systolic left ventricular diameters, only a minority of our patients were expected to experience reverse remodeling. RESULTS: Regurgitation is none to trivial in 31 and mild to moderate in 4. Follow-up (3-84 months; mean, 55 +/- 22 months) shows stability of all initially successful double-level mitral repairs. Follow-up beyond 1 year shows improvements in ventricular diameters (56 +/- 5 mm), ejection fraction (49 +/- 6), volume (130 +/- 10 mL), and sphericity index (0.55). Two patients died during follow-up and 1 underwent transplantation. CONCLUSION: Reapproximating the papillary muscles has an immediate effect on mitral leaflet mobility by suppressing the tethering resulting from displacement of the papillary muscles. It has an effect in preventing recurrent mitral regurgitation by avoiding further papillary muscle displacement. In this cohort of severely disabled patients, reverse remodeling can be expected with the double-level repair.

In vitro study of percutaneous aortic valve replacement: selection of a tissue valve.

BACKGROUND: Selection of the best tissue valve is an essential step before percutaneous aortic valve replacement (PAVR) becomes a clinical reality. The aim of this study was to evaluate in vitro three different tissue valves mounted within the same endovascular stent. METHODS: Thirty stented valves (10 aortic porcine, 10 pulmonary porcine, and 10 pericardial tubular) were sutured within a 32-mm long by 23-mm diameter cobalt-nickel stent. The porcine valves were trimmed down close to the cusps. All valves were delivered with a percutaneous valvuloplasty catheter and placed orthotopically in a latex root that was cast from a sheep's aorta. The roots were tested in a pulse duplicator at a rate of 60 beats per minute and 3.5 liters per minute. The transvalvular gradient, maximum valve orifice area, and presence of central and paravalvular leaks were recorded echocardiographically. RESULTS: Within the limitations of implantation in a synthetic, noncalcified annulus, the pericardial valve performed best in terms of orifice area, transvalvular gradients, and tissue bulk; but four of the ten valves showed a central leak due to the type of stent used. CONCLUSION: The ideal valve for PAVR should collapse with minimal bulk to avoid coronary obstruction and central and paravalvular leaks. The tubular pericardial valve showed the lowest pressure gradients and was the most compressible, but was more open to manufacturing errors.

Redo aortic root surgery for failure of an aortic homograft is a major technical challenge.

OBJECTIVE: Aortic homografts offer many advantages over prosthetic valves. However, homograft dysfunction due to degeneration or infection may lead to reoperation. Aortic valve replacement in patients who have undergone previous aortic root replacement with an aortic homograft remains a technical challenge. To assess reoperation events a retrospective review was conducted. MATERIALS AND METHODS: From January 2000 to October 2006, 20 consecutive patients (38.8+/-14.9 years old) underwent repeat surgery for aortic homograft failure. RESULTS: Reoperation was performed 7.2+/-3.5 years after implantation of the aortic homograft as a root. Indication was homograft degeneration (n=18 [90%]) and endocarditis (n=2 [10%]). In patients with major homograft wall calcifications or endocarditis, nine aortic root reconstructions were performed (Bentall procedure n=7; homograft implantation n=2). Each homograft was dissected with electrical cauterization and removed 'en-bloc' sparing the coronary buttons. In case of flexible homograft wall, stented prostheses (mechanical n=10, bioprosthesis n=1) were implanted along the homograft annulus. Additional procedures consisted of mitral valve replacements (n=8), tricuspid repairs (n=4), Konno procedure (n=1) and coronary bypass (n=5). Perioperative complications occurred in seven (35%) patients: sternal re-entry accident (n=2); reoperations for mediastinitis (n=1) or bleeding (n=2); renal insufficiency (n=1); total heart block (n=1). No association was found between operative procedures and postoperative complications (Fisher's exact test). Two patients (10%) died from multiorgan failure in the early postoperative period. In total, 94.4% of the survivors remained free from reoperation at 74 months. CONCLUSION: Reoperation on patients with an aortic homograft as a root presents a relatively high perioperative morbidity. The surgical strategy depends on the degree of homograft wall calcification.

A lesional classification to standardize surgical management of aortic insufficiency towards valve repair.

OBJECTIVE: Aortic valve repair is an alternative to valve replacement for treatment of chronic aortic insufficiency (AI). In order to standardize surgical management, we suggest a classification based on echocardiographic and operative analysis of valvular lesions. METHODS: Classification was based on the retrospective analysis of chronic AI mechanisms of 781 adults operated on electively between 1997 and 2003. RESULTS: AI was isolated (406 patients (52%)), associated with supra-coronary aneurysm (97 cases (12.4%)), or with aortic root aneurysm (278 patients (35.6%)). Etiologies of valvular or aortic lesions were respectively rheumatic, dystrophic and atheromatous in 17%, 73.6% and 9.4% of cases. Lesional classification is based on the analysis of chronic AI mechanisms defining type I with central jet (354 cases, 45.3%) and type II with eccentric jet (54.7%). Type Ia is defined as isolated dilation of sino-tubular junction (47 supra-coronary aneurysms), and type Ib as dilation of both sino-tubular junction and aortic annular base (233 root aneurysms, 74 isolated AI). The type II associates dilation of sino-tubular junction and annular base to a valvular lesion: IIa cusp prolapse (95 aneurysms, 200 isolated AI); IIb cusp retraction (132 rheumatic AI), IIc cusp tear (endocarditis, traumatic). CONCLUSION: A lesional classification aims to standardize the surgical management of aortic valve repair: type Ia, by supra-coronary graft; type Ib, by subvalvular aortic annuloplasty associated with the aortic root replacement with a remodelling technique (root aneurysm) or double sub- and supravalvular annuloplasty (isolated AI). For chronic AI type II, aortic annuloplasty associated a remodelling technique or double sub- and supravalvular annuloplasty is combined with the treatment of the cusp lesion (cusp resuspension, cusp reconstruction with autologous pericardium).

[Evolution of the surgical strategy in hypertrophic cardiomyopathy: case studies of eight patients]. / Cardiomyopathie hypertrophique, évolution de la stratégie chirurgicale: à propos de huit patients.

INTRODUCTION: Hypertrophic cardiomyopathy is an inherited disease characterized by a left ventricular hypertrophy, a diastolic dysfunction and rhythm troubles with risk of sudden death. There was an evolution in the surgical strategy to treat the patients who present a left ventricular outflow tract gradient. MATERIALS AND METHODS: A retrospective study was conducted: We selected eight cases who presented an hypertrophic cardiomyopathy and operated on. Pre and post operative echocardiographic data were analysed. Follow up was obtained by call or mail to the cardiologist. RESULTS: The patients were classified in four groups: isolated left ventricular outflow tract obstruction, left ventricular outflow tract obstruction and associated lesions, obstructive hypertrophic cardiomyopathy and endocarditis, post operative complications of the hypertrophic cardiomyopathy surgery. We observed a significant decrease of the left ventricular outflow tract mean gradient in the post operative period and at four years. CONCLUSION: Surgical management of obstructive hypertrophic cardiomyopathy remain an important option in young patients, in case of failure of the ethanol septal ablation or in patients who present other surgical lesions. The dual chamber stimulation remain indicated in old patients.

Dimensional ratios of normal mitral valve structures: a tool for determining the degree of geometric distortion in individual patients.

BACKGROUND AND AIM OF THE STUDY: One objective of mitral valve repair is to restore the distorted mitral apparatus geometry to its normal dimensions specific for each patient. Because all dimensions of the normal aortic and mitral valves should be related, it was hypothesized that, in the presence of a normal aortic annulus, it would be possible to determine the dimensions of the structures needed for mitral valve repair. METHODS: In seven sheep, sonometric ultrasound crystals were implanted at the left and right trigones (T1, T2), lateral annulus (P1, P2), and the tips of the anterior and posterior papillary muscles (Ml, M2). The distances T1-T2, M1-M2, T1-M1, T2-M2, P1-P2, P1-M1, and P2-M2 were measured at end-systole (ES), end-diastole (ED), and maximum and minimum lengths. Using these measured distances, fractional relationships were computed, and the average fractional relationship was used to determine a 'calculated' distance. The 'measured' and 'calculated' distances were then compared using a paired t-test. RESULTS: All fractional relationships were close to 1, with ED 1.00 +/- 0.21, ES 0.99 +/- 0.19, maximum length 0.99 +/- 0.19, and minimum length 0.94 +/- 0.21. The intertrigonal distance (T1-T2) expanded by 4.19 +/- 3.81%, and the transverse diameter (P1-P2) contracted by -6.15 +/- 3.69% from ED to ES. The interpapillary muscle distance (M1-M2) contracted -22.3 +/- 6.5%. The two distances with the least amount of contraction were those of T1-M1 and T2-M2, with contractions of -3.06 +/- 2.39% and -3.27 +/- 1.37%, respectively. P1-M1 and P2-M2 expanded 5.60 +/- 2.89% and 6.84 +/- 3.60% from ED to ES. CONCLUSION: The mitral valve dimensions and calculated fractional relationships were similar in all sheep. As shown previously, the ratio of aortic annulus diameter (easily measured echocardiographically) to the intertrigonal distance (T1-T2) is 0.79 and 0.80 in humans and sheep, respectively. This distance can be used to determine normal mitral valve geometry and, therefore, preoperatively to calculate the degree of geometric distortion present in individual patients.

Coronary flow obstruction in percutaneous aortic valve replacement. An in vitro study.

OBJECTIVE: Coronary flow obstruction is a serious complication reported in percutaneous aortic valve replacement. In an in vitro study of porcine hearts, the effects of valved stent implantation on coronary artery flow were studied with the native valve's leaflets intact and excised. METHODS: The right and left main coronary arteries of porcine hearts were dissected 20mm distal to the aortic root and directed into lengths of latex tubing leading to collection flasks. The ascending aorta was cut proximal to the brachiocephalic trunk, cannulated, and attached to a constant-head water supply. After steady flow was achieved, the flow rate from each coronary artery was measured. In Group A (n=10), a tubular pericardial valve sutured into a cylindrical, cobalt-nickel stent was deployed orthotopically using a valvuloplasty balloon catheter. In Group B (n=10), the native leaflets were removed before similar valve deployment. Coronary flow measurements were repeated post-implantation. RESULTS: In Group A, valve implantation resulted in a significant decrease in both left and right coronary flows. In Group B, no significant change in either right or left coronary flow was found after valve placement. CONCLUSION: Implantation of a percutaneous valved stent in the orthotopic position with the native valve in place causes coronary ostial obstruction. This problem highlights the need for modified stents that are designed for implantation in patients with non-retracted, fibrotic, or calcified leaflets.

The papillary muscles as shock absorbers of the mitral valve complex. An experimental study.

OBJECTIVE: Although it is known that the papillary muscles ensure the continuity between the left ventricle (LV) and the mitral apparatus, their precise mechanism needs further study. We hypothesize that the papillary muscles function as shock absorbers to maintain a constant distance between their tips and the mitral annulus during the entire cardiac cycle. MATERIALS AND METHODS: Sonomicrometry crystals were implanted in five sheep in the mitral annulus at the trigones (T1 and T2), mid anterior annulus (AA) mid posterior annulus (PA), base of the posterior lateral scallops (P1 and P2), tips of papillary muscles (M1 and M2), and LV apex. LV and aortic pressures were simultaneously recorded and used to define the different phases of the cardiac cycle. RESULTS: No significant distance changes were found during the cardiac cycle between each papillary muscle tip and their corresponding mitral hemi-annulus: M1-T1, (3.5+/-2%); M1-P1 (5+/-2%); M1-PA (5+/-3%); M2-T2 (2.7+/-2%); M2-P2 (6.1+/-3%); and M2-AA (4.2+/-3%); (p>0.05, ANOVA). Significant changes were observed in distances between each papillary muscle tip and the contralateral hemi-mitral annulus: M1-T2 (1.7+/-3%); M1-P2 (23+/-6%); M1-AA (6+/-3%); M2-T1 (8+/-3%); M2-P1 (10.5+/-6%); and M2-PA (12.6+/-8%); (p<0.05 ANOVA). The distance changes between LV apex and each papillary muscle tip were significantly different: apex-M1 (12.9+/-1%) and apex-M2 (10.5+/-1%) and different from the averaged distance change between the LV apex and each annulus crystal (8.3+/-1%) with p<0.05. CONCLUSION: The papillary muscles seem to be independent mechanisms designed to work as shock absorbers to maintain the basic mitral valve geometry constant during the cardiac cycle.

Sutureless stented aortic valve implantation under direct vision: lessons from a negative experience in sheep.

BACKGROUND AND AIM OF THE STUDY: Percutaneous aortic valve replacement has been proposed as a valid alternative to surgery in selected cases; however, it still has many problems. As a less radical preliminary step, we implanted a balloon-expandable stented aortic valve under direct vision in sheep. METHODS: Under cardiopulmonary bypass (CPB) and through a transverse aortotomy, an aortic valve mounted in a long tubular balloon-expandable stent was implanted in six acute sheep. The leaflets were not excised and no anchoring sutures were used between stent and native annulus. Epicardial, two-dimensional color Doppler echocardiography was used to assess the function of the stented valve followed by macroscopic inspection at necropsy. RESULTS: Direct visualization of the entire annulus when the collapsed, valved stent was placed within the aortic root was difficult in all animals. Valve deployment took less than 1 minute. The surgical procedure resulted in major complications in all cases. Migration (3/6), paravalvular leak (2/6), mitral conflicts resulting in mitral regurgitation (1/6), and coronary ostia obstruction (2/6) were the major events at the origin of the failure. Only three animals could be weaned from CPB but did not recover enough to survive the procedure. CONCLUSIONS: Sutureless implantation of a stented aortic valve through standard CPB and aortotomy is far more complex than expected. Changes in stent design and surgical approach are indicated.

Evidence of mitigated calcification of the Mosaic versus Hancock Standard valve xenograft in the mitral position of young sheep.

OBJECTIVES: Durability remains the main problem of all bioprosthetic valves, and calcification is the major cause of failure. New tissue treatment processes are expected to reduce mineralization. A comparative animal study was undertaken to evaluate the behavior of a new-generation porcine bioprosthesis in contrast with a first-generation porcine bioprosthesis. The primary goal was to evaluate the efficacy of alpha-amino-oleic acid as an anticalcification treatment. METHODS: Seventeen Targhee sheep (aged 4.5-7 months) had a mitral valve replacement with a Mosaic or Hancock Standard. The animals were followed up to 20 weeks (144.1 +/- 4.0 days vs 144.3 +/- 8.2 days) and then euthanized as scheduled. After gross examination, the explants were radiographed for the presence of calcification. The central portions were preserved for histologic examination, and the remainder of the sample was analyzed for quantitative calcium content by atomic absorption spectroscopy. RESULTS: Four Mosaic sheep were excluded because of perioperative surgical mortality. The remaining 13 were enrolled in the study (9 Mosaic and 4 Hancock Standard). The mean calcium content was 1.97 +/- 2.21 microg/mg tissue weight for Mosaic versus 8.36 +/- 4.12 microg/mg for Hancock Standard valves (P < .01). Mild fibrous tissue overgrowth and fibrinous lining were observed regardless the xenograft type. CONCLUSIONS: The low level of calcification in the Mosaic versus Hancock Standard xenografts confirms the efficacy of alpha-amino-oleic acid treatment in mitigating mineralization. A longer durability is expected with the clinical use of the Mosaic porcine valve.

Functional terminology for the tricuspid valve.

BACKGROUND AND AIM OF THE STUDY: Advances in echocardiography have awoken new interest in the tricuspid valve, which otherwise has been largely ignored by cardiologists and surgeons. These advances demand a precise terminology for the description of the tricuspid valve's different anatomic structures in health and disease. While simple nomenclatures have been developed for the mitral valve, no such system has been described for the tricuspid valve. METHODS: In order to develop a tricuspid valve terminology similar to the existing mitral valve nomenclature, a study of 50 porcine hearts was conducted. The study was designed not as a strict anatomical description but rather as a search for common parameters between both valves. The findings were based on the traditional understanding that the tricuspid valve has three main leaflets and three papillary muscles. The leaflets were defined according to their heights (free edge to base) and their chordal insertions. The papillary muscles were grouped according to the distribution of their chords to a commissure and its contiguous main leaflets. RESULTS: In all hearts, three main leaflets were found: septal (S), anterior (A), and posterior (P), associated with a variable number of commissural leaflets (C). Three groups of papillary muscles could be identified: anteroseptal with a mean of 1.78 muscles (range: 1-4), anteroposterior with 1.08 muscles (range: 1-4), and posteroseptal with 2.42 muscles (range: 1-5). Each group was identified (counterclockwise) with the numerals 1 (anteroseptal), 2 (posteroseptal), and 3 (anteroposterior). Each half of the leaflets and their corresponding commissures were identified by the initial letter of their classic name (S, A, P, or C) and their supporting papillary muscle group (1, 2, or 3). CONCLUSION: This system provides a method for reporting echocardiographic and surgical findings for the tricuspid valve. The system parallels previously described mitral valve nomenclature. This unified terminology should facilitate the precise recording of echocardiographic and surgical data.

An experimental method for the percutaneous induction of a posterolateral infarct and functional ischemic mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: Appropriate experimental models are needed to study the mechanisms underlying left ventricular (LV) remodeling and functional ischemic mitral regurgitation (IMR). Herein is described an original percutaneous method for inducing a well-defined posterolateral infarct and significant IMR. METHODS: Under videofluoroscopic guidance, the second (OM2) and third (OM3) obtuse marginal branches of the circumflex artery of six sheep were selectively and sequentially injected with 100% ethyl alcohol. Transthoracic echocardiography (TTE) was performed before and after alcohol injection, and weekly until sacrifice at 8 +/- 1.3 weeks. The LV endsystolic (LVESD) and end-diastolic (LVEDD) dimensions, interpapillary distance (M1-M2), mitral annulus diameter (MA), and degree of IMR and ischemic tricuspid regurgitation (ITR) were measured. RESULTS: One animal died from irreversible ventricular fibrillation. In the remaining sheep, a well-defined posterolateral infarct of 22% of the heart mass resulted, followed by 2.8 + IMR and 2.1+ ITR. The mean weight gain was 16%, and all sheep showed signs of heart failure. All echocardiographic parameters were increased: systolic MA by 29%, diastolic MA by 18%, LVEDD by 33%, LVESD by 62%, M1-M2 diastolic by 32%, M1-M2 systolic by 21%, and tethering and tenting distances by 32% and 108%, respectively. CONCLUSION: The percutaneous selective injection of 100% ethyl alcohol in OM2 and OM3 resulted in a well-defined posterolateral infarct and significant IMR and ITR. Because it was a percutaneous procedure, this novel, simple and reproducible method did not require a thoracotomy. This model should facilitate the further study of LV remodeling and IMR.